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Sex Differences in the Stress Response

Dr. Galea has been studying sex differences in response to stress since 1997.

Females exhibit different patterns of neural and behavioural responses to stress than males (Galea et al., 1997; Barha et al., 2007; Barha et al., 2010). Work in my laboratory has found that exposure to chronic stress results in different phenotypes for males and females. We have also found that gonadal hormones can reduce resilience to stress in BOTH males and females. Castration in males or withdrawal from a hormone-stimulated pregnancy or long-term ovariectomy was associated with the development of depressive-like symptoms in response to stress (males: Wainwright et al., 2011; females: Green & Galea, 2008; Green et al., 2009; Mahmoud et al., 2016). These data indicate that sex differences in the behavioural and neural response to stress are partly mediated by gonadal hormones. Translational work, with Tim Oberlander, examined the effects of the selective serotonin reuptake inhibitor (SSRI) exposure and maternal mood during gestation on neuroplastic markers in infants (Pawluski et al., 2009; Brummelte et al., 2012). We are currently examining the influence of maternal immune signaling during the late postpartum on maternal depression with Tim Oberlander in humans. We found that antidepressants increased the density of immature neurons (doublecortin-ir) but only in adult depressed women and not in depressed men (Epp et al., 2013). Recent work has examined the effects of estrogens on inflammatory signaling following stress (Eid et al., 2019; 2020).  We now have used this knowledge to understand how treatments such as SSRIs, DREADDS, and inflammatory antagonists alter depressive endophenotypes in males and females, and in females under different reproductive states. Our new CIHR work is centered on negative cognitive bias, a cognitive symptom of major depressive disorder. We have found that there are sex differences in functional connectivity, neurogenesis in the hippocampus, as well as hippocampal and basolateral amygdala inflammation in response to cognitive bias testing (Hodges et al., 2022a; Hodges et al., 2022b). Our new work is examining the mechanism of negative cognitive bias following chronic unpredictable stress. We also plan to examine the mechanisms of hormone-induced stress resilience using transcriptome (neurons versus microglia) after chronic stress in both sexes, building on our findings that estrogens and androgens provide stress resilience in both sexes (Eid et al., 2020; Mahmoud et al., 2016; Wainwright et al., 2011, 2014).

Sex Differences in Neural and Molecular and Neural Mechanisms Underlying Negative Cognitive Bias. (funded by CIHR)

The goal of this work is to determine the mechanisms underlying sex differences in negative cognitive bias in a model of depression. Females are twice more likely to develop major depressive disorder (MDD) compared to males. Cognitive symptoms of MDD, such as negative cognitive bias, are more severe in females than in males. Negative cognitive bias is the increased perception of ambiguous situations as negative and predicts the onset of future depressive episodes. Current treatments are only effective for a subset of the population and are not effective at reducing negative cognitive bias. Cognitive bias involves pattern separation, which relies on adult hippocampal neurogenesis, the connectivity between the hippocampus and amygdala, and is impaired by inflammatory signaling via IL-1β and we find sex differences in each of these factors with negative cognitive bias.


The goal of this work is to examine sex differences in the neural and molecular underpinnings of negative cognitive bias after CUS. Neuroinflammation and hippocampal neurogenesis modulate pattern separation which underlies negative cognitive bias, suggesting a previously unexplored connection between these factors. Our pilot work indicates negative bias is associated with immune markers in females, but with neuroplastic markers in males and that targeting glutamate receptors in the ventral hippocampus has opposing effects on negative cognitive bias (increasing it in females and decreasing it in males). The discovery of underlying mechanisms of negative cognitive bias in both sexes will facilitate the development of precision medicine for MDD.

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